Alzheimer's Disease and AD-related dementias (ADRDs) (Frontotemporal Dementia, Lewy Body Dementia, etc.) are devastating neurodegenerative disorders whose onset is correlated with age. Due to the increase of human life span in the 20th century, Alzheimer's and ADRDs have become a major medical, societal and economic issue of today. In spite of decades of research and clinical efforts, cures have been elusive, and Alzheimer's has become the 6th cause of death in the USA. New hypotheses, mechanisms and drug targets for Alzheimer's and ADRDs are urgently needed. One promising direction is inflammation: aging and many age-related diseases are thought to be causally linked with a chronic inflammatory state known as inflammaging. Alzheimer's is no exception, and neuroinflammation establishes an environment in the brain that is hostile for the function and survival of neurons. While it is not yet clear if neuroinflammation is a cause of Alzheimer's, it is increasingly believed that alleviating neuroinflammatory processes might slow down Alzheimer's Disease progression. Cell senescence is an irreversible arrest of proliferation due to a variety of stresses. It is characterized by the secretion of proinflammatory molecules, the senescence associated secretory phenotype (SASP). The paracrine effect of the SASP on surrounding cells is a key mechanism by which senescent cells promote age-associated diseases. Essentially all brain cells, including astrocytes, microglia and neurons, can become senescent. The frequency of senescent cells increases in Alzheimer's and ADRDs. Removing senescent cells in mouse models of Alzheimer's reduces neuroinflammation, alleviates pathology and improves cognitive function. We discovered a novel mechanism which maintains and propagates cell senescence, and thus inflammation. Retrotransposable elements (RTEs), known as Long Interspersed Nuclear Elements (LINE-1, or L1) are activated in senescent cells and induce a type-I interferon (IFN-I) response, which in turn drives the SASP. The IFN-I response is triggered by innate immune system DNA sensors that detect cytoplasmic L1 cDNAs, whose synthesis can be blocked by nucleoside reverse transcriptase inhibitor (NRTI) drugs. NRTIs were developed to treat HIV, and several well- tolerated drugs potently inhibit the L1 reverse transcriptase (RT). On the basis of this evidence we hypothesize that L1 activation is an important component of Alzheimer's neuroinflammation and that L1 is a relevant drug target for the treatment of Alzheimer's and ADRDs. We propose the following Specific Aims: 1) To investigate the genesis of L1 cDNAs in the cytoplasm of senescent cells. This will define new targets and target engagement assays for NRTI treatment of neuroinflammation in Alzheimer's. 2) To apply NRTI therapy to mouse models of Alzheimer's and other neurodegenerative diseases. Due to their good blood-brain barrier penetration NRTI drugs hold great promise for the treatment of Alzheimer's and ADRDs. Aim 3: To assess the efficacy of available NRTIs to inhibit L1, as well as to develop new drugs against L1-encoded enzymes. In aggregate, this research will shed new light on the mechanisms of neuroinflammation and advance new treatments for Alzheimer's and ADRDs.